Proposed is a continuation of a productive program of research that has the overall goal of elucidating the mechanism(s) underlying cognitive decline with aging. To achieve this goal, we originally organized and will continue a program of research that includes 4 research projects, 3 essential core facilities and a group of talented investigators. The research program is driven by the now strongly supported hypothesis that oxidative stress in the brain leads to age-related oxidative damage and is a major determinant of the rate of cognitive aging. As such the 4 research projects focus on a systematic assessment of these issues. Project 1 will determine the role of now identified age-related oxidation sensitive proteins and highly significant shifts in the redox state of most brain regions in cognitive decline with age. Project 2 will determine the role of and mechanism by which insult-induced decline in protein phosphates results in persistent activation of a number of kinases, and oxidative stress that leads to AD-neuropathology and cognitive decline. Project 3 will determine the mechanisms underlying the function of immediate early gene products that control intracellular Ca2+ channels and intracellular Ca2+ homeostasis during cognitive aging and oxidative stress in the CNS. Project 4 will assess the signaling mechanism(s) by which the important ovarian steroid, progesterone, enhances LTP and reduces cognitive decline with aging, with a focus on its effects on NMDA receptors. All of these research projects are interactive in their mechanistic focus on the overall hypothesis of the program, the sharing of ideas, tissues, and the use of behavioral assessments following insults or interventions as important functional readouts in animal models shared and employed by all projects. This is achieved through an Administration Core (Core A) that will oversee the program and provide biostatistical support, an Animal Resources and Behavioral and Assessment Core (Core B) that will provide care for and behaviorally characterize all animal models and an Electrophysiology Core (Core C) that will provide assessment of the effects of age, genotypes, insults or interventions on an electrophysiological signature of memory and learning, LTP. This mechanistically driven and statistically-validated, multidisciplinary program of research, that focuses on determining critical molecular and functional mechanisms that underlie cognitive aging, will enhance our understanding of the role of oxidative stress in cognitive aging, and generate potential targets for effective intervention.